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WO1993021190A1 - Procede de preparation et de purification de melanges de phospholipides non contamines par des virus non classiques - Google Patents

Procede de preparation et de purification de melanges de phospholipides non contamines par des virus non classiques Download PDF

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Publication number
WO1993021190A1
WO1993021190A1 PCT/EP1993/000915 EP9300915W WO9321190A1 WO 1993021190 A1 WO1993021190 A1 WO 1993021190A1 EP 9300915 W EP9300915 W EP 9300915W WO 9321190 A1 WO9321190 A1 WO 9321190A1
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WIPO (PCT)
Prior art keywords
mixture
phospholipid
process according
components
meg
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PCT/EP1993/000915
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English (en)
Inventor
Alessandro Di Martino
Lanfranco Callegaro
Gino Toffano
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Fidia SpA
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Fidia SpA
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Priority to DE69308834T priority Critical patent/DE69308834D1/de
Priority to EP93911469A priority patent/EP0638083B1/fr
Publication of WO1993021190A1 publication Critical patent/WO1993021190A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/30—Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/10—Phosphatides, e.g. lecithin
    • C07F9/103—Extraction or purification by physical or chemical treatment of natural phosphatides; Preparation of compositions containing phosphatides of unknown structure

Definitions

  • the present invention relates to a process for the preparation of phospholipid mixtures which selectively eliminates contaminants associ- 5 ated with potentially pathogenic unconventional viruses, without altering the biological and pharmacological characteristics of the mixture.
  • Extracts from bovine brain have been used as 10 therapeutic agents for many years.
  • purified phospholipids represent the active principle of a large number of pharmacological specialties.
  • Experimental and clinical documentation of the pharmacological properties of phospholipids have been available 5 for many years (Bruni A. et al. , Nature 260, 331, 1976; Hirata F. et al. , Nature 275, 219, 1978; Delwaide P.J. et al. , Acta Neurol. Scand. 73, 136, 1986) .
  • BSE bovine spongiform encephalopathy
  • the disease is so called because of the 5 spongy appearance of the brain tissue of affected animals when observed under a microscope; the main lesions are constituted by extensive intraneuronal vacuolation.
  • BSE 10 belongs to the group of degenerative encephalopathies of the central nervous system, caused by the family of unconventional, transmissible agents whose outcome is invariably fatal (Fraser et al. , Vet. Record 123: 472, 1988; 15 Hope et al., Nature 336: 390, 1988).
  • diseases include scrapie of sheep and goats, the chronic wasting disease (CWD) which affects captive mule deer, transmissible mink encephalopathy affecting animals on mink ranches, 20 and three human diseases: kuru, Creutzfeldt-Jakob disease (CJD) and the Gerstmann-Stra ⁇ ssler- Scheinker syndrome (GSS) .
  • the histopathological lesions found in brains affected by these diseases are similar to those caused by BSE. 25 Many theories have been put forward as to the nature of these etiological agents, which are different from any known infectious agent, and therefore known as unconventional agents. Due to the long incubation period between infection and the onset of clinical symptoms, they are also known as "slow viruses".
  • 20 BSE could be transmitted by the oral route. No other tissue from infected animals (spleen, spinal cord, lymphatic tissues, milk etc.) has been able to produce the disease in mice. While evidence exists that scrapie can be transmitted
  • the etiological agent of scrapie is highly resistant to temperature sterilization. Prolonged exposure to temperatures of up to 80°C 10 only slightly reduces their infectivity; higher temperatures however markedly reduce infectivity (Hunter et al, J. Gen. Microbiol. 37: 251,1964). A small quantity of infectious "virus" remains viable when suspensions of infected material are 15 heated to 100°C for l hour or to 118°C for 10 minutes. Recently the need was felt to update standards of sterilizing these infectious agents by steam autoclaving.
  • the purpose of the present invention is to provide a product in pharmacologically active form and, at the same time, being characterized
  • the product deriving from 5 this process is constituted by a definite mixture of phospholipids or single fractions obtained from bovine brain or parts of the same.
  • the nervous tissue is preferably derived from bovine brain.
  • step A) said nervous tissue material is subjected to an extraction with a solvent mixture including a chlorinated hydrocarbon to obtain a first raw phospholipid-comprising mixture, subjecting said first raw phospholipid-comprising mixture a further purification step, and isolating the 5 further purified product.
  • the suspension of the phospholipid mixture to be loaded on a silica gel column has been prepared by a method comprising the steps of 10 a) extracting bovine brain to obtain a crude extract comprising phospholipids, b) filtering said crude extract to obtain a filtrate, c) adding a precipitating agent to said 15 filtrate to obtain a precipitate, d) isolating said precipitate to obtain said first raw phospholipid-comprising mixture, e) purifying said first raw mixture to
  • step a) is conducted with 25 a mixture of organic solvents such as acetone in combination with chlorinated hydrocarbons, especially 1,1,1-trichloroethane.
  • the extraction is performed under vigorous stirring for an extended period of time, e.g. 30-60 minutes.
  • the temperature is preferably room temperature.
  • the suspension is centrifuged, whereby insoluble material and the upper acetone- comprising phase were discarded.
  • the crude extract is then iltered according to step b) .
  • step a precipitating agent such as acetone
  • step d) the precipitate is isolated in step d) by means of centrifugation.
  • 15 product is the first raw material (phospholipid- comprising mixture) .
  • Said first raw material is redissolved in a solvent mixture comprising a chlorinated hydrocarbon such as 1,1,1- trichloroethane in admixture with an alcohol such
  • step e) of the first raw material is performed by the addition of water, shaking the mixture for a period of 30-90 minutes, preferably 60 minutes,
  • This second 10 raw material may be further purified by the addition of a saline to a suspension of the second raw material in a chlorinated hydrocarbon such as chloroform in admixture with an alcohol such as methanol.
  • a chlorinated hydrocarbon such as chloroform
  • an alcohol such as methanol.
  • the mixture of aqueous and 15 non-aqueous solvents comprising the second raw material is then shaken for 15-30 minutes at room temperature. Centrifugation of the two phases and recovery of the organic phase yields a solution of the desired phospholipid mixture.
  • the phospholipids can be precipitated by means of acetone; in order to ensure full precipitation the mixture may be left standing for a period of time of 30-60 minutes at a temperature below room temperature, e.g. at 13-17°C, preferably 15°C.
  • the alternative purification method for purification consists of loading the material derived from nervous tissue on a silica gel column.
  • the column is pre-washed with a 5 chlorinated hydrocarbon such as chloroform before the nervous tissue derived material is loaded - thereon.
  • the elution of the desired phospholipid mixture is performed with the chlorinated hydrocarbon, preferably chloroform, to which is 10 added one or more alcohols and water.
  • the alcohol is selected from the group consisting of methanol, ethanol, propanols, butanols and pentanols.
  • the elution is performed with eluents in e.g. the following sequence: chloroform, 15 chloroform/ethanol, chloroform/methanol/water
  • the second raw material from step e) is suspended in a' 25 suitable liquid comprising a chlorinated hydrocarbon such as chloroform and an alcohol such as methanol.
  • a chlorinated hydrocarbon such as chloroform
  • an alcohol such as methanol.
  • the suspension is loaded on a silica gel column and eluted as described above. After the elution the desired end product is recovered from the eluting solvents, preferably by means of vacuum drying.
  • An especially preferred process variant 5 consists of extraction of phospholipids from bovine brain by a mixture of chlorinated solvents, for example 1,1,1-trichloroethane, and acetone, at room temperature and for at least 30 minutes; or silica gel chromatography of a
  • the product is a phospholipid mixture comprising at least two components selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, plasmalogen choline,
  • the phospholipid preparable by the invention comprises only a single phospholipid fraction
  • the bovine brains used in the process of extraction of the phospholipid mixture showed, on istological analysis r the fibrils typical for 5 tissues belonging to materials from animals with the infection.
  • the animals were examined twice a week or
  • the infective titer was calculated at the "final end point" according to the method of Reed and Munch, and is expressed as log LD 50 /ml.
  • Figure 1 illustrates an example of the compositions of the phospholipid mixture purified as described.
  • FIGURE 1 A first figure.
  • Lane 1 standard phospholipid phosphatidylethanolamine (PE) Lane 2: standard phospholipid phosphatidic acid (PA) 20 Lane 3: standard phospholipid phosphatidylinositol (PI) Lane 4: standard phospholipid phosphatidylserine (PS) Lane 5: standard phospholipid 25 phosphatidylcholine (PC) Lane 6: standard phospholipid sphingomyelin
  • the phospholipid mixture obtained as 5 described and free from contaminants associated with unconventional, potentially dangerous infective agents, can also be used for the preparation of single components of the phospholipid mixture, such as phosphatidylserine.
  • compositions which are efficacious in numerous pathologies (with different etiopathogenic causes) in particular of the central nervous system and the immune system,
  • degenerative pathologies associated with immune dysfunctions The following can be cited: psychoorganic syndromes characterized by involution or cerebrovascular insufficiencies, behavioral impairments correlated with neuroendocrine alterations, depressive syndromes, anxious-depressive states, degenerative 5 pathologies also associated with immune dysfunctions, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, encephalitis of various origin, and in pathologies associated with alterations in
  • compositions according to the present invention can be administered by oral or parenteral route, preferably by intramuscular route, by intravenous injection or by infusion.
  • the preparations can be as solutions of the compound (or freeze-dried powders of the compound) in association with one or more pharmaceutically acceptable vectors or diluents and contained in buffered media with a suitable
  • Safe storage of the pharmaceutical can be ensured by packing it in vials, ampoules, capsules, single dose packets, as described in the following examples of pharmaceutical
  • the dose of active substance depends on the desired effects and on the chosen route of administration and can be between 0.05 and 12 mg/kg body weight of the patient per dose, corresponding to a daily administration of between about 5 and 2000 mg to an adult human.
  • Another aspect of the present invention relates to a method for the treatment of pathologies of the central nervous system and degenerative pathologies also associated with immune system dysfunctions comprising the
  • a mixture of phospholipids prepared according to the invention may have the following
  • composition 30-50% phosphatidylcholine, 24-44% phosphatidylethanolamine, 7-13% phosphatidyl ⁇ serine, and 11-27% phosphatidylinositol and minor phospholipids.
  • compositions such preparations may have the following composition (expressed in meg of phosphorus, per 50 mg of mixture) : 280- 420 meg P as phosphatidylcholine, 140-210 meg P as phosphatidylethanolamine, 140-210 meg P as
  • phosphatidylserine 8-12 meg P as plasmalogen choline, 68-102 meg P as plasmalogen ethanolamine, 40-60 meg P as plasmalogen serine, 10-24 meg P as phosphatidic acid, 28-42 meg P as diphosphoinositide and 68-102 meg P as sphingomyelin.
  • composition of a mixture of 5 phospholipids prepared according to the invention can be as follows (expressed in meg of phosphorous per 100 meg of total phosphorous) : 25-45 meg phosphatidylcholine, 12-22 meg P as phosphatidylethanolamine, 12-22 meg P as
  • phosphatidylserine 0.5-1.5 meg P as plasmalogen choline, 5-13 meg P as plasmalogen ethanolamine, 2-8 meg P as plasmalogen serine, 1-3 meg P as phosphatidic acid, 2-6 meg P as diphospho ⁇ inositide and 5-13 meg P as sphingomyelin.
  • examples 1-3 describe preparations made from infected bovine brains where the spongiform encephalopathy form was encountered or from protein raw materials
  • EXAMPLE 1 5 1000 grams of infected frozen bovine brain, were ground to a fine powder. A small aliquot of powder was removed for the infectivity test and stored at -70°C.
  • All of the powder was dispersed in 900 ml of 10 acetone for 15-30 minutes at room temperature.
  • the samples for biological assay were recovered in sterile PBS in the following
  • Table 1 reports an example of the results obtained by assay of the biological activity.
  • the column was eluted with chloroform, chloroform/ethanol in the ratio 7:3, chloroform/methanol/water (65:25:4) and chloroform/methanol/water (50:50:12.5) (12.5 parts of water per volume) in turn.
  • Each 25 fraction was recovered for analysis by TLC chromatography (V.P. Skipski et al., Methods Enzymol., 14, 1969: 530; F, Vitiello et al., J. Chromatogr. , 166, 1978: 637).
  • the fractions eluted with chloroform/methanol/water (65:25:4) (4 parts of water per volume), corresponding to fractions 12-18, were recovered and vacuum-dried. They were then resuspended by 5 sonication in PBS.
  • Tab-le 2 reports an example of the results obtained by assay of the biological activity.
  • the column marked "sample” reports the number of animals inoculated at the start of the experiment and the cage number relative to each different sample and dilution.
  • the column marked "sick animals” reports the number of animals with clinical signs of scrapie/number of animals inoculated minus the number of animals that died of causes other than scrapie.
  • the sample was well shaken to disperse the aqueous phase and 10 ⁇ l were taken for biological assay (starting material) .
  • the sample was then loaded into a column where it was eluted with the following solvents and their mixtures: chloroform, chloroform/ethanol, (7:3) chloroform/methanol/water, (65:25:4) and chloroform/methanol/water (50:50:12.5) (12.5 parts of water in the organic phase volume) .
  • the rate of flow through the column was between 3 and 10 ml/min, preferably 6 ml min, and fractions of 2 ml each were taken. $*. - -
  • Fraction 1-8 Column front, cholesterol esters, cerebrosides Fraction 9-11 Sulfatides and traces of 5 phosphatidylcholine
  • Table 3 reports an example of the results obtained by assay of biological activity.
  • hypothalamic phospholipid liposomes corresponding to micrograms of lipidic phosphorous 400 5 - phosphatidylcholine 40% phosphatidylethanolamine + phosphatidylserine 34% sphingomyelin 10% other phospholipids present in small 10 quantities (phosphatidylinositol, diphosphoinositide, phosphatidic acid, lysolecithin, lysocephalin) 16%
  • EXAMPLE 5 20
  • One 2-ml ampoule contains: hypothalamic phospholipid liposomes corresponding to micrograms of lipidic phosphorous 1000 phosphatidylcholine 40% phosphatidylethanolamine + 25 phosphatidylserine 34% sphingomyelin 10% other phospholipids present in small quantities (phosphatidylinositol, diphosphoinositide, phosphatidic acid, lysolecithin, lysocephalin) 16%
  • One 2-ml ampoule contains:
  • the outer shell is constituted by:
  • One 2-ml ampoule contains: 5 - phosphatidylserine 50.00 mg
  • One 2-ml ampoule contains: phosphatidylserine 50.00 mg
  • mannitol 50.00 mg dibasic sodium phosphate-12H 2 0 1.13 mg monobasic sodium phosphate-2H 2 0 1.07 mg water for injection q.s. ad 1 ml
  • One capsule contains: phosphatidylserine 100.00 mg
  • the outer shell is constituted by: gelatin 129.00 mg glycerol 49.00 mg rust brown E 172 1.10 mg rust red E 172 0.40 mg
  • One capsule contains:
  • the outer shell is constituted by:
  • One single-dose pack (granules for oral use to mix with water before use) contains: phosphatidylserine 100.00 mg Other components:
  • One single-dose pack (granules for oral use to mix with water before use) contains: 25 - phosphatidylserine 100.00 m
  • Other components sodium ascorbate 5.00 mg aspartame 5.00 mg colloidal silica 10.00 mg
  • One single-dose pack (granules for oral use to

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Abstract

On peut préparer un mélange de phospholipides dont les propriétés biologiques et pharmacologiques restent intactes alors qu'on a éliminé les virus non classiques provoquant par exemple l'encéphalopathie spongiforme bovine. Dans ce procédé de préparation on procède à l'extraction de phospholipides provenant d'un cerveau de bovin à l'aide d'un mélange de solvants organiques comprenant au moins un hydrocarbure chloré ou au moyen d'une chromatographie sur gel de silice comprenant l'élution avec une succession d'éluants tels que du chloroforme, des alcools inférieurs et de l'eau, ou bien encore en associant l'extraction et la chromatographie sur gel de silice. Ces phospholipides purifiés peuvent être utilisés dans des compositions pharmaceutiques.
PCT/EP1993/000915 1992-04-17 1993-04-16 Procede de preparation et de purification de melanges de phospholipides non contamines par des virus non classiques Ceased WO1993021190A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE69308834T DE69308834D1 (de) 1992-04-17 1993-04-16 Verfahren zur herstellung und reinigung von phospholipidmischungen frei von kontaminierenden unkonventionellen viren
EP93911469A EP0638083B1 (fr) 1992-04-17 1993-04-16 Procede de preparation et de purification de melanges de phospholipides non contamines par des virus non classiques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITPD920073A IT1260149B (it) 1992-04-17 1992-04-17 Metodo per la preparazione e purificazione di miscele di fosfolipidi prive di contaminanti da virus non convenzionali
ITPD92A000073 1992-04-17

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WO1993021190A1 true WO1993021190A1 (fr) 1993-10-28

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WO (1) WO1993021190A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000077A1 (fr) * 1994-06-27 1996-01-04 Institut De Recherche Biologique Nouvelles utilisations d'un complexe a base de phospholipides cerebraux en therapeutique et dans l'alimentation
JPH08332030A (ja) * 1993-12-31 1996-12-17 Inst De Rech Biolog 幼児の栄養摂取のための新規食物添加物
FR2736265A1 (fr) * 1995-07-07 1997-01-10 Forgeot Marcel Nouvelles compositions a base de phosphoglycero ethers et leur utilisation dans le traitement des maladies neuro-degeneratives
FR2746030A1 (fr) * 1996-03-15 1997-09-19 Pasteur Merieux Serums Vacc Procede pour eliminer les agents transmissibles non conventionnels (atnc) d'une solution d'albumine
WO1997034642A1 (fr) * 1996-03-15 1997-09-25 Pasteur Merieux Serums Et Vaccins Procede pour eliminer les agents transmissibles non conventionnels d'une solution proteique
FR2750887A1 (fr) * 1996-07-09 1998-01-16 Imedex Procede d'elimination des agents transmissibles non conventionnels (atnc) d'une solution proteique
WO2003088949A3 (fr) * 2002-04-19 2004-12-16 Bioghurt Biogarde Gmbh & Co Kg Matrice a constituant bioactif contenant des phospholipides
WO2006128639A3 (fr) * 2005-05-30 2007-08-09 Fidia Farmaceutici Procede de preparation et d'isolation des phosphatides
DE10250727B4 (de) * 2002-04-19 2008-07-10 Cargill, Incorporated, Wayzata Matrix mit einer bioaktiven Phospholipid-haltigen Komponente
CN114989212A (zh) * 2022-05-27 2022-09-02 广州白云山汉方现代药业有限公司 一种天然鞘磷脂的制备方法
CN115010748A (zh) * 2022-05-27 2022-09-06 扬州大学 硅胶柱层析同时分离纯化磷脂酰胆碱和鞘磷脂的方法
IT202100032252A1 (it) * 2021-12-22 2023-06-22 Fidia Farm Spa Processo di estrazione e purificazione industriale di fosfolipidi

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0148045A1 (fr) * 1983-11-17 1985-07-10 FIDIA S.p.A. Compositions pharmaceutiques et procédé de préparation de compositions contenant de la phosphatidylsérine pour le traitement des troubles du système nerveux central sans effets sur la coagulation du sang
EP0150712A2 (fr) * 1984-01-04 1985-08-07 Bioiberica, S.A. Méthode d'obtention d'un complexe de glycosphingoslipide
WO1991007417A1 (fr) * 1989-11-17 1991-05-30 Fidia S.P.A. Procede pour la preparation et la purification d'un melange de glycosphingolipides exempts de contamination par des virus non traditionnels

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0148045A1 (fr) * 1983-11-17 1985-07-10 FIDIA S.p.A. Compositions pharmaceutiques et procédé de préparation de compositions contenant de la phosphatidylsérine pour le traitement des troubles du système nerveux central sans effets sur la coagulation du sang
EP0150712A2 (fr) * 1984-01-04 1985-08-07 Bioiberica, S.A. Méthode d'obtention d'un complexe de glycosphingoslipide
WO1991007417A1 (fr) * 1989-11-17 1991-05-30 Fidia S.P.A. Procede pour la preparation et la purification d'un melange de glycosphingolipides exempts de contamination par des virus non traditionnels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 101, no. 22, 26 November 1984, Columbus, Ohio, US; abstract no. 198172c, page 377 ; *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08332030A (ja) * 1993-12-31 1996-12-17 Inst De Rech Biolog 幼児の栄養摂取のための新規食物添加物
WO1996000077A1 (fr) * 1994-06-27 1996-01-04 Institut De Recherche Biologique Nouvelles utilisations d'un complexe a base de phospholipides cerebraux en therapeutique et dans l'alimentation
AU701528B2 (en) * 1994-06-27 1999-01-28 Institut De Recherche Biologique Novel therapeutic and dietetic uses of a brain phospholipid-based complex
FR2736265A1 (fr) * 1995-07-07 1997-01-10 Forgeot Marcel Nouvelles compositions a base de phosphoglycero ethers et leur utilisation dans le traitement des maladies neuro-degeneratives
WO1997002828A1 (fr) * 1995-07-07 1997-01-30 Sarl Institut D'hygiene Et Dietetique Nouvelles compositions a base de phosphoglycero-ethers et leur utilisation dans le traitement des maladies neuro-degeneratives
US5759585A (en) * 1995-07-07 1998-06-02 S.Ar.L. Institut D'hygiene Et Dietetique Plasmalogen compositions and their use in neurodegenerative diseases treatment
FR2746030A1 (fr) * 1996-03-15 1997-09-19 Pasteur Merieux Serums Vacc Procede pour eliminer les agents transmissibles non conventionnels (atnc) d'une solution d'albumine
WO1997034642A1 (fr) * 1996-03-15 1997-09-25 Pasteur Merieux Serums Et Vaccins Procede pour eliminer les agents transmissibles non conventionnels d'une solution proteique
US6372510B1 (en) 1996-03-15 2002-04-16 Pasteur Merieux Serum Et Vaccins Method for removing unconventional transmissible agents from a protein solution
FR2750887A1 (fr) * 1996-07-09 1998-01-16 Imedex Procede d'elimination des agents transmissibles non conventionnels (atnc) d'une solution proteique
WO2003088949A3 (fr) * 2002-04-19 2004-12-16 Bioghurt Biogarde Gmbh & Co Kg Matrice a constituant bioactif contenant des phospholipides
DE10250727B4 (de) * 2002-04-19 2008-07-10 Cargill, Incorporated, Wayzata Matrix mit einer bioaktiven Phospholipid-haltigen Komponente
WO2006128639A3 (fr) * 2005-05-30 2007-08-09 Fidia Farmaceutici Procede de preparation et d'isolation des phosphatides
US7759095B2 (en) 2005-05-30 2010-07-20 Fidia Farmaceutici S.P.A. Process for the preparation and isolation of phosphatides
EP2431020A1 (fr) * 2005-05-30 2012-03-21 Fidia Farmaceutici S.p.A. Procédé de séparation et purificatio de phosphatidylsérine
IT202100032252A1 (it) * 2021-12-22 2023-06-22 Fidia Farm Spa Processo di estrazione e purificazione industriale di fosfolipidi
WO2023119129A1 (fr) * 2021-12-22 2023-06-29 Fidia Farmaceutici S.P.A. Procédé industriel d'extraction et de purification de phospholipides
CN114989212A (zh) * 2022-05-27 2022-09-02 广州白云山汉方现代药业有限公司 一种天然鞘磷脂的制备方法
CN115010748A (zh) * 2022-05-27 2022-09-06 扬州大学 硅胶柱层析同时分离纯化磷脂酰胆碱和鞘磷脂的方法
CN115010748B (zh) * 2022-05-27 2023-10-20 扬州大学 硅胶柱层析同时分离纯化磷脂酰胆碱和鞘磷脂的方法

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ATE150025T1 (de) 1997-03-15
EP0638083A1 (fr) 1995-02-15
IT1260149B (it) 1996-03-28
DE69308834D1 (de) 1997-04-17
EP0638083B1 (fr) 1997-03-12
ITPD920073A0 (it) 1992-04-17
ITPD920073A1 (it) 1993-10-17

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